WO2019063320A1 - Composition comprenant une protéine bactéricide/augmentant la perméabilité et de l'acide hyaluronique pour le traitement d'arthropathies - Google Patents

Composition comprenant une protéine bactéricide/augmentant la perméabilité et de l'acide hyaluronique pour le traitement d'arthropathies Download PDF

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Publication number
WO2019063320A1
WO2019063320A1 PCT/EP2018/074889 EP2018074889W WO2019063320A1 WO 2019063320 A1 WO2019063320 A1 WO 2019063320A1 EP 2018074889 W EP2018074889 W EP 2018074889W WO 2019063320 A1 WO2019063320 A1 WO 2019063320A1
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Prior art keywords
bpi
hyaluronic acid
composition
bactericidal
composition according
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Inventor
Leonardo PUNZI
Anna SCANU
Roberto LUISETTO
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Universita degli Studi di Padova
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Universita degli Studi di Padova
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1751—Bactericidal/permeability-increasing protein [BPI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to the pharmaceutical and biological field.
  • compositions comprising
  • BPI Bactericidal/permeability increasing protein
  • HA hyaluronic acid
  • arthropathy comprises more than 100 different conditions that may affect individuals of all ages, genders and ethnicities. All these conditions are characterized by joint pain accompanied by stiffness and swelling and in case of arthritis, by inflammation. All these diseases are the leading cause of disability in the USA and in Europe.
  • treatments for arthropathies aim at reducing pain, inflammation and preventing permanent joint damage.
  • Bactericidal/permeability-increasing protein is a cationic protein with high antimicrobial activity. It is produced and released in extracellular fluids mainly by polymorphonuclear cells, but can be also expressed in fibroblasts and epithelial cells (Reichel PH, Seemann C, Csernok E, Schroder JM, M jller A, Gross WL, Schultz H. Bactericidal/permeability-increasing protein is expressed by human dermal fibroblasts and upregulated by interleukin 4.
  • BPI selectively and specifically acts against infections caused by gram-negative bacteria by damaging bacterial membranes, neutralizing lipopolysaccharide (LPS), and opsonizing bacteria to enhance their phagocytosis by polymorphonuclear leukocytes (PMN)
  • PMN polymorphonuclear leukocytes
  • BPI inhibits angiogenesis inducing cell apoptosis, inhibiting migration of endothelial cells and complexing the vascular endothelial growth factor (VEGF) (van der Schaft DW, Toebes EA, Haseman JR, Mayo KH, Griffioen AW.
  • VEGF vascular endothelial growth factor
  • Bactericidal/permeability-increasing protein (BPI) inhibits angiogenesis via induction of apoptosis in vascular endothelial cells. Blood 2000;96:176-81 ; van der Schaft DW, Wagstaff J, Mayo KH, Griffioen AW.
  • BPI may interact with some membrane receptors, such as toll-like receptor 4 (TLR4) and glypican 4 (Canny G, Cario E, Lennartsson A, Gullberg U, Brennan C, Levy O, Colgan SP. Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein.
  • TLR4 toll-like receptor 4
  • glypican 4 Canny G, Cario E, Lennartsson A, Gullberg U, Brennan C, Levy O, Colgan SP.
  • Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein Am J PhysiolGastrointest Liver Physiol 2006;290:G557-67; Geraldes P, Yamagata M, Rook SL, Sassa Y, Ma RC, Clermont A, Gao B, Aiello LP, Feener EP, King GL.
  • Glypican 4 a membrane binding protein for bactericidal/permeability-increasing protein signaling pathways in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2007;48:5750-5). BPI has been detected in high amount in synovial fluid of patients with reactive arthritis and rheumatoid arthritis, and to lower extent in psoriatic arthritis and osteoarthritis however its specific role in these different types of arthropathies has not been defined yet (Punzi L, Peuravuori H, Jokilammi-Siltanen A, Bertazzolo N, Nevalainen TJ. Bactericidal/permeability increasing protein and proinflammatory cytokines in synovial fluid of psoriatic arthritis.
  • BPI is able to inhibit the inflammatory processes induced by pathogenic crystals that are found in some arthropathies by reducing the leukocyte recruitment and cytokine production (Scanu A, Luisetto R, Oliviero F, Galozzi P, Ramonda R, Punzi L. Bactericidal/permeability-increasing protein downregulates the inflammatory response to pathogenic crystals in vitro and in vivo. Ann Rheum Dis 2017;76(supplement 2):210).
  • WO9420128 describes some therapeutic uses of BPI, including the treatment of chronic inflammatory diseases, such as arthritis.
  • Hyaluronic acid is widely used for viscosupplementation of joints. Studies have reported that HA may also exhibit anti-inflammatory, analgesic and chondroprotective effects.
  • BPI Bactericidal/permeability-increasing protein
  • hyaluronic acid has a very advantageous effect in the treatment of arthropathies, in particular there is a greater effect compared to the effect of BPI or hyaluronic acid used individually.
  • said combination showed to be significantly effective in reducing inflammation and clinical signs in animals with induced experimental arthritis.
  • composition comprising Bactericidal/permeability-increasing protein (BPI) and hyaluronic acid.
  • BPI Bactericidal/permeability-increasing protein
  • composition as a medicament.
  • composition comprising Bactericidal/permeability-increasing protein (BPI) and hyaluronic acid for use in the treatment of an arthropathy.
  • BPI Bactericidal/permeability-increasing protein
  • said arthropathy is selected from the group consisting of degenerative arthropathies, post-traumatic arthropathies, metabolic arthropathies, crystal-induced arthropathies, inflammatory arthropathies, septic arthritis and reactive arthritis.
  • composition comprising as active agents at least the Bactericidal/permeability-increasing protein (BPI) and hyaluronic acid together with at least one pharmaceutically acceptable carrier and/or excipient.
  • BPI Bactericidal/permeability-increasing protein
  • compositions for use in the treatment of an arthropathy comprising as active agents at least the Bactericidal/permeability-increasing protein (BPI) and hyaluronic acid and at least one pharmaceutically acceptable carrier and/or excipient.
  • BPI Bactericidal/permeability-increasing protein
  • hyaluronic acid at least one pharmaceutically acceptable carrier and/or excipient.
  • BPI Bactericidal/permeability-increasing protein
  • a further object of the present invention is a kit including:
  • BPI Protein Bactericidal/permeability-increasing
  • said kit is for use as a medicament, in particular for the treatment of an arthropathy.
  • BPI Bactericidal/permeability- increasing protein
  • hyaluronic acid in an inflammatory condition, such as monosodium urate and calcium pyrophosphate crystal-induced inflammation, for example in gout and in pseudogout, is able to significantly reduces the total white blood cell count, the percentage of polymorphonuclear cells and inhibit the production of the inflammatory mediators evaluated.
  • arthropathy means any joint disease.
  • Bactericidal/permeability-increasing protein'Or “BPI” means a known protein of about 50 kDa, which is produced by the immune system.
  • Bactericidal/permeability-increasing protein” or “BPI” means any Bactericidal/permeability-increasing protein produced through natural, synthetic or recombinant methods; comprising also its natural, synthetic and recombinant biologically active polypeptide fragments; and biologically active polypeptides or their BPI analogues.
  • biologically active fragments are fragments of BPI protein retaining the biological activity, such as fragment 1 -199, fragment 200-456 (Ooi CE, Weiss J, Elsbach P, Frangione B, Mannion B.
  • a 25-kDa NH2-terminal fragment carries all the antibacterial activities of the human neutrophil 60-kDa bactericidal/permeability-increasing protein. J BiolChem 1987;262:14891-4) fragment 13-191 (Horwitz AH, Ammons WS, Bauer RJ, Dedrick R, Nadell R, Williams RE, Liu PS.
  • rBPI(10-193) is secreted by CHO cells and retains the activity of rBPI21.
  • biologically active analogues are recombinant analogue of BPI protein retaining the biological activity such as rBPI23 (Jellema WT1 , Veerman DP, De Winter RJ, Wesseling KH, Van Deventer SJ, Farm CE, van Lieshout JJ.
  • rBPI23 Jellema WT1 , Veerman DP, De Winter RJ, Wesseling KH, Van Deventer SJ, hack CE, van Lieshout JJ.
  • rBPI23 recombinant bactericidal/permeability-increasing protein
  • hyaluronic acid or “hyaluronan” means the known glycosaminoglycan which is a major component of human and animal connective tissue and comprising a disaccharide polymer composed of glucuronic acid and N-acetyl-glucosamine.
  • Hyaluronic acid is also herein referred by the acronym HA.
  • composition of the invention comprises a protein known as Bactericidal/permeability-increasing protein (BPI).
  • BPI Bactericidal/permeability-increasing protein
  • the invention also comprises biological, synthetic or recombinant biological fragments of BPI, with the proviso that the biological functionality of the protein is maintained.
  • BPI Biologically active analogs of BPI may also be used, such as BPI in which one or more amino acids have been replaced without alteration of biological activity.
  • the molecule may lack of one or more N-terminal amino acids, one or more internal amino acids and/or one or more carboxy-terminal amino acids.
  • BPI analogs may also be recombinant hybrid fusion proteins comprising BPI or its biologically active fragments and at least a portion of one or more other polypeptides, such as the heavy chain constant region of an immunoglobulin or an allelic variant thereof.
  • Said fragments or analogs can easily be obtained by the expert in the field based on his common general knowledge. For example, they can be generated synthetically or isolated using methods known in the art.
  • fragments can be fragment 1 -199, fragment 200-456, fragment 13-191.
  • recombinant analogues can be rBPI21 , rBPI23.
  • BPI or its fragments or analogs may also be in the monomeric, dimeric or multimeric form.
  • the other component of the composition is hyaluronic acid.
  • Hyaluronic acid also called hyaluronan
  • hyaluronic acid can be used in any of its known forms, in particular it can be a polymer of any chain length and molecular dimension.
  • it can refer to low molecular weight, high molecular weight, cross- linked and/or esterified hyaluronic acid, and/or a salt thereof (hyaluronate) and/or an amine derivative thereof. All these forms are well known in the art and commercially available or obtainable through common knowledge in the field.
  • the two components can be present in the composition of the invention in any ratio.
  • the ratio between BPI and hyaluronic acid is comprised between 1 :0.001 and 1 :1000. More preferably, said ratio is comprised between 1 :0.005 and 1 :100. Even more preferably, the ratio between the amounts by weight of the two components is about 1 :4 (BPI:HA).
  • BPI is preferably administered at a dose ranging from 0.01 to 10 ⁇ g g of body weight, more preferably at a dose ranging from 0.1 to 5 ⁇ g g of body weight, even more preferably at a dose comprised between 0.2 and 1 .5 ⁇ g g of body weight.
  • the dose of BPI is about 1.43 ⁇ g g of body weight; in another preferred embodiment, the BPI dose is about 0.29 ⁇ g g of body weight.
  • the hyaluronic acid is preferably present in the composition in an amount, expressed as weight/volume%, comprised between 0.01 and 10% with respect to the total composition, more preferably in an amount ranging from 0.1 to 1 % with respect to the total of composition. In a preferred embodiment, hyaluronic acid is in the amount of about 0.02% with respect to the total composition.
  • composition described above can be used as a medicament.
  • it is for use in the treatment of arthropathies.
  • Arthropathies can be, for example, degenerative arthropathies, including osteoarthritis; post-traumatic arthropathies, resulting from physical trauma; arthropathies from infection, including reactive arthritis and septic arthritis; primary inflammatory arthropathies, including rheumatoid arthritis and psoriatic arthritis; crystal-induced arthritis, such as gout and pseudogout; metabolic arthropathies associated with metabolic diseases; para- or extra-articular rheumopathies.
  • degenerative arthropathies including osteoarthritis
  • post-traumatic arthropathies resulting from physical trauma
  • arthropathies from infection including reactive arthritis and septic arthritis
  • primary inflammatory arthropathies including rheumatoid arthritis and psoriatic arthritis
  • crystal-induced arthritis such as gout and pseudogout
  • metabolic arthropathies associated with metabolic diseases para- or extra-articular rheumopathies.
  • the composition is for use in the treatment of arthritis.
  • the composition can be administered to a subject affected by the aforesaid pathologies by conventional methods.
  • said medicament is in the form of a preparation for parenteral administration, but other forms are equally suitable for implementing the present invention.
  • Injection in particular intra-articular injection, is a preferred route of administration.
  • composition of the invention are administered in a therapeutic effective amount.
  • the expert in the field will decide the effective timing of administration, depending on the patient's condition, the disease severity, the patient's response and any other clinical parameter included in the general knowledge of this field.
  • the therapeutically effective dose for each compound can be initially estimated in cell culture assays or in animal models, usually mice, rats, guinea pigs, dogs or pigs.
  • the animal model can also be used to determine the appropriate dose range and the route of administration. This information can be used to determine doses and routes of administration that are useful for humans. It is recommended to use the conversion table provided in the document Guidance for Industry and Reviewers (2002, US Food and Drug Administration, Rockville, Maryland, USA) to calculate the Human Equivalent Dose (HED).
  • An average dose for human administration can be established during clinical trials, as is customary in the field.
  • the specific effective dose for a human subject will depend on the disease severity, the general health of the subject, the age, the weight and the sex of the subject, the diet, the time and frequency of administration, the possible combinations of drugs and the tolerance/response to therapy. This amount can be determined by routine testing and is part of the physician evaluation.
  • composition comprising as active ingredients at least the Bactericidal/permeability-increasing protein (BPI) and hyaluronic acid together with at least one pharmaceutically acceptable carrier and/or excipient.
  • BPI Bactericidal/permeability-increasing protein
  • compositions will contain as active agents at least the BPI, or its biologically active fragments or analogs, and hyaluronic acid.
  • compositions according to the present invention contain, together with the active ingredient, at least one pharmaceutically acceptable carrier or excipient.
  • formulation adjuvants such as, for example, solubilizing agents, dispersing agents, suspending agents and emulsifying agents.
  • compositions according to the present invention may also contain one or more further active ingredients.
  • This active ingredient can be, for example, a compound useful for the treatment of arthropathies, for example a compound that reduces pain, reduces inflammation and/or prevents joint damage.
  • a compound useful for the treatment of arthropathies for example a compound that reduces pain, reduces inflammation and/or prevents joint damage.
  • anti-inflammatory such as traditional non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, painkillers, opioid or non-opioid analgesics, which can be appropriately selected by the expert in the field depending on the desired effect.
  • Average amounts of active compound may vary and in particular should be based on the recommendations and prescription of a qualified physician.
  • the administration regimen, dosage and route of administration will be decided by the physician based on their experience, the disease to be treated and patient conditions.
  • the form of the compositions will be solid or liquid, suitable for oral or parenteral administration, in particular for intra-articular administration.
  • the pharmaceutical composition of the invention is for use as a medicament.
  • it is for use in the treatment of an arthropathy, preferably selected from those described above.
  • composition of the invention may also be in the form of a kit comprising as component a) Bactericidal/permeability-increasing protein (BPI) and as component b) hyaluronic acid.
  • BPI Bactericidal/permeability-increasing protein
  • component b) hyaluronic acid In this case, the two components can be administered simultaneously or in any sequence.
  • BPI Bactericidal/permeability-increasing protein
  • the two substances can be administered by means of a single composition comprising both the active ingredients or by means of two separate compositions, one for each active ingredient, administered simultaneously or sequentially, in any order.
  • the expert in the field will be able to choose the most appropriate therapy, timing and dosage by referring to his general knowledge in the field.
  • MSU monosodium urate
  • CPP calcium pyrophosphate
  • MSU and CPP crystals were prepared by Denko's (Denko CW, Whitehouse MW.
  • mice were sacrificed after 3 h by an excess of anesthesia (inhalation of sevoflurane at 8%) and peritoneal fluids were harvested by washing with 2 mL of PBS. Immediately after, lavage fluids, collected with eventually present exudate, were assessed for total and differential white blood cell (WBC) count to determine the inflammation degree.
  • WBC white blood cell
  • IL interleukin
  • CXCL1 chemokine(C-X-C motif) ligand 1
  • TNF tumor necrosis factor
  • VEGF vascular endothelial growth factor
  • results Injection of suspension of MSU or CPP crystals induced an inflammatory response, with a peak after 3 hours, involving leukocyte recruitment, mainly polymorphonuclear cells (PMN), and increased the levels of ⁇ _-1 ⁇ , CXCL1 , IL-6, TNF and VEGF in lavage fluids collected.
  • PMN polymorphonuclear cells
  • Results are reported in the following table 1.
  • the grey areas refer to the use of a composition according to the invention.
  • CII type II collagen
  • CFA complete Freund's adjuvant
  • the remaining blood was centrifuged at 3000 rpm for 10 min to obtain serum and the levels of IL-1 ⁇ , IL-6, CXCL1 , TNF and VEGF were measured by ELISA.
  • CIA is a well-established experimental model that through an autoimmune reaction to a cartilage component can lead to a chronic destructive polyarthritis.
  • Histological analysis confirms the development of arthritis and shows the typical features of CIA, including synovial inflammation, leukocyte infiltration, cartilage damage, bone resorption, pannus formation.
  • mice injected with HA alone All parameters evaluated indicated a tendency towards a decrease in mice injected with HA alone as compared with untreated controls.
  • Results are reported in tables 3 and 4.
  • the grey areas refer to the use of a composition according to the invention.

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Abstract

La présente invention concerne une composition comprenant une protéine bactéricide/augmentant la perméabilité (BPI) et de l'acide hyaluronique. Cette composition offre des avantages significatifs dans le traitement d'arthropathies. La présente invention concerne également des compositions pharmaceutiques et des kits comprenant la protéine bactéricide/augmentant la perméabilité (BPI) et de l'acide hyaluronique, en particulier pour le traitement d'arthropathies.
PCT/EP2018/074889 2017-09-27 2018-09-14 Composition comprenant une protéine bactéricide/augmentant la perméabilité et de l'acide hyaluronique pour le traitement d'arthropathies Ceased WO2019063320A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IT102017000108102 2017-09-27
IT102017000108102A IT201700108102A1 (it) 2017-09-27 2017-09-27 Composizione di bactericidal/permeability increasing protein e acido ialuronico per il trattamento delle artropatie
IT201800003756 2018-03-19
IT102018000003756 2018-03-19

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WO2019063320A1 true WO2019063320A1 (fr) 2019-04-04

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Citations (4)

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Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
WO1994020128A1 (fr) 1993-03-12 1994-09-15 Xoma Corporation Utilisations therapeutiques de produits proteiques augmentant le pouvoir bactericide et/ou la permeabilite
US5639727A (en) * 1993-03-12 1997-06-17 Xoma Corporation Therapeutic uses of bactericidal/permeability increasing protein products
US20030194377A1 (en) * 1996-11-01 2003-10-16 Carroll Stephen Fitzhugh Therapeutic uses of BPI protein products in cystic fibrosis patients
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US20130084268A1 (en) * 2008-02-15 2013-04-04 Bone Therapeutics Pharmaceutical composition for use in the treatment and/or the prevention of osteoarticular diseases

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